Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene
Identifieur interne : 000284 ( Main/Corpus ); précédent : 000283; suivant : 000285Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene
Auteurs : Matthias Elstner ; Christopher M. Morris ; Katharina Heim ; Peter Lichtner ; Andreas Bender ; Divya Mehta ; Claudia Schulte ; Manu Sharma ; Gavin Hudson ; Stefano Goldwurm ; Alessandro Giovanetti ; Massimo Zeviani ; David J. Burn ; Ian G. Mckeith ; Robert H. Perry ; E. Jaros ; Rejko Krüger ; H. Rich Wichmann ; Stefan Schreiber ; Harry Campbell ; James F. Wilson ; Alan F. Wright ; Malcolm Dunlop ; Giorgio Pistis ; Daniela Toniolo ; Patrick F. Chinnery ; Thomas Gasser ; Thomas Klopstock ; Thomas Meitinger ; Holger Prokisch ; Douglass M. TurnbullSource :
- Annals of Neurology [ 0364-5134 ] ; 2009-12.
Abstract
Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798
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DOI: 10.1002/ana.21780
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title><author><name sortKey="Elstner, Matthias" sort="Elstner, Matthias" uniqKey="Elstner M" first="Matthias" last="Elstner">Matthias Elstner</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Morris, Christopher M" sort="Morris, Christopher M" uniqKey="Morris C" first="Christopher M." last="Morris">Christopher M. Morris</name><affiliation><mods:affiliation>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Heim, Katharina" sort="Heim, Katharina" uniqKey="Heim K" first="Katharina" last="Heim">Katharina Heim</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Bender, Andreas" sort="Bender, Andreas" uniqKey="Bender A" first="Andreas" last="Bender">Andreas Bender</name><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Mehta, Divya" sort="Mehta, Divya" uniqKey="Mehta D" first="Divya" last="Mehta">Divya Mehta</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Goldwurm, Stefano" sort="Goldwurm, Stefano" uniqKey="Goldwurm S" first="Stefano" last="Goldwurm">Stefano Goldwurm</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Giovanetti, Alessandro" sort="Giovanetti, Alessandro" uniqKey="Giovanetti A" first="Alessandro" last="Giovanetti">Alessandro Giovanetti</name><affiliation><mods:affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Zeviani, Massimo" sort="Zeviani, Massimo" uniqKey="Zeviani M" first="Massimo" last="Zeviani">Massimo Zeviani</name><affiliation><mods:affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Mckeith, Ian G" sort="Mckeith, Ian G" uniqKey="Mckeith I" first="Ian G." last="Mckeith">Ian G. Mckeith</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Perry, Robert H" sort="Perry, Robert H" uniqKey="Perry R" first="Robert H." last="Perry">Robert H. Perry</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Jaros, E" sort="Jaros, E" uniqKey="Jaros E" first="E." last="Jaros">E. Jaros</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wichmann, H Rich" sort="Wichmann, H Rich" uniqKey="Wichmann H" first="H. Rich" last="Wichmann">H. Rich Wichmann</name><affiliation><mods:affiliation>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schreiber, Stefan" sort="Schreiber, Stefan" uniqKey="Schreiber S" first="Stefan" last="Schreiber">Stefan Schreiber</name><affiliation><mods:affiliation>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><affiliation><mods:affiliation>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><affiliation><mods:affiliation>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Wright, Alan F" sort="Wright, Alan F" uniqKey="Wright A" first="Alan F." last="Wright">Alan F. Wright</name><affiliation><mods:affiliation>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Dunlop, Malcolm" sort="Dunlop, Malcolm" uniqKey="Dunlop M" first="Malcolm" last="Dunlop">Malcolm Dunlop</name><affiliation><mods:affiliation>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Pistis, Giorgio" sort="Pistis, Giorgio" uniqKey="Pistis G" first="Giorgio" last="Pistis">Giorgio Pistis</name><affiliation><mods:affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><affiliation><mods:affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</mods:affiliation></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klopstock, Thomas" sort="Klopstock, Thomas" uniqKey="Klopstock T" first="Thomas" last="Klopstock">Thomas Klopstock</name><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Prokisch, Holger" sort="Prokisch, Holger" uniqKey="Prokisch H" first="Holger" last="Prokisch">Holger Prokisch</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Turnbull, Douglass M" sort="Turnbull, Douglass M" uniqKey="Turnbull D" first="Douglass M." last="Turnbull">Douglass M. Turnbull</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1002/ana.21780</idno><idno type="url">https://api.istex.fr/document/2BC3F834E82888B9EB2A98E42CFBDD319BDDB254/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000284</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title><author><name sortKey="Elstner, Matthias" sort="Elstner, Matthias" uniqKey="Elstner M" first="Matthias" last="Elstner">Matthias Elstner</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Morris, Christopher M" sort="Morris, Christopher M" uniqKey="Morris C" first="Christopher M." last="Morris">Christopher M. Morris</name><affiliation><mods:affiliation>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Heim, Katharina" sort="Heim, Katharina" uniqKey="Heim K" first="Katharina" last="Heim">Katharina Heim</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Bender, Andreas" sort="Bender, Andreas" uniqKey="Bender A" first="Andreas" last="Bender">Andreas Bender</name><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Mehta, Divya" sort="Mehta, Divya" uniqKey="Mehta D" first="Divya" last="Mehta">Divya Mehta</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Goldwurm, Stefano" sort="Goldwurm, Stefano" uniqKey="Goldwurm S" first="Stefano" last="Goldwurm">Stefano Goldwurm</name><affiliation><mods:affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Giovanetti, Alessandro" sort="Giovanetti, Alessandro" uniqKey="Giovanetti A" first="Alessandro" last="Giovanetti">Alessandro Giovanetti</name><affiliation><mods:affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Zeviani, Massimo" sort="Zeviani, Massimo" uniqKey="Zeviani M" first="Massimo" last="Zeviani">Massimo Zeviani</name><affiliation><mods:affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Mckeith, Ian G" sort="Mckeith, Ian G" uniqKey="Mckeith I" first="Ian G." last="Mckeith">Ian G. Mckeith</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Perry, Robert H" sort="Perry, Robert H" uniqKey="Perry R" first="Robert H." last="Perry">Robert H. Perry</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Jaros, E" sort="Jaros, E" uniqKey="Jaros E" first="E." last="Jaros">E. Jaros</name><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Wichmann, H Rich" sort="Wichmann, H Rich" uniqKey="Wichmann H" first="H. Rich" last="Wichmann">H. Rich Wichmann</name><affiliation><mods:affiliation>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation></author><author><name sortKey="Schreiber, Stefan" sort="Schreiber, Stefan" uniqKey="Schreiber S" first="Stefan" last="Schreiber">Stefan Schreiber</name><affiliation><mods:affiliation>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</mods:affiliation></affiliation></author><author><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><affiliation><mods:affiliation>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><affiliation><mods:affiliation>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Wright, Alan F" sort="Wright, Alan F" uniqKey="Wright A" first="Alan F." last="Wright">Alan F. Wright</name><affiliation><mods:affiliation>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Dunlop, Malcolm" sort="Dunlop, Malcolm" uniqKey="Dunlop M" first="Malcolm" last="Dunlop">Malcolm Dunlop</name><affiliation><mods:affiliation>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Pistis, Giorgio" sort="Pistis, Giorgio" uniqKey="Pistis G" first="Giorgio" last="Pistis">Giorgio Pistis</name><affiliation><mods:affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</mods:affiliation></affiliation></author><author><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><affiliation><mods:affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</mods:affiliation></affiliation><affiliation><mods:affiliation>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</mods:affiliation></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation><mods:affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klopstock, Thomas" sort="Klopstock, Thomas" uniqKey="Klopstock T" first="Thomas" last="Klopstock">Thomas Klopstock</name><affiliation><mods:affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Prokisch, Holger" sort="Prokisch, Holger" uniqKey="Prokisch H" first="Holger" last="Prokisch">Holger Prokisch</name><affiliation><mods:affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Turnbull, Douglass M" sort="Turnbull, Douglass M" uniqKey="Turnbull D" first="Douglass M." last="Turnbull">Douglass M. Turnbull</name><affiliation><mods:affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-12">2009-12</date><biblScope unit="volume">66</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="792">792</biblScope><biblScope unit="page" to="798">798</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</idno><idno type="DOI">10.1002/ana.21780</idno><idno type="ArticleID">ANA21780</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Matthias Elstner MD</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string><json:string>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</json:string></affiliations></json:item><json:item><name>Christopher M. Morris PhD</name><affiliations><json:string>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Katharina Heim BSc</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Peter Lichtner PhD</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Andreas Bender MD</name><affiliations><json:string>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</json:string></affiliations></json:item><json:item><name>Divya Mehta MSc</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Claudia Schulte MSc</name><affiliations><json:string>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Manu Sharma PhD</name><affiliations><json:string>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Gavin Hudson PhD</name><affiliations><json:string>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Stefano Goldwurm MD, PhD</name><affiliations><json:string>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</json:string></affiliations></json:item><json:item><name>Alessandro Giovanetti MSc</name><affiliations><json:string>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</json:string></affiliations></json:item><json:item><name>Massimo Zeviani MD, PhD</name><affiliations><json:string>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</json:string></affiliations></json:item><json:item><name>David J. Burn MD, FRCP</name><affiliations><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Ian G. McKeith MD</name><affiliations><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Robert H. Perry MD</name><affiliations><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>E. Jaros PhD</name><affiliations><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Rejko Krüger MD</name><affiliations><json:string>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>H.‐Erich Wichmann MD, PhD</name><affiliations><json:string>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string></affiliations></json:item><json:item><name>Stefan Schreiber MD</name><affiliations><json:string>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</json:string></affiliations></json:item><json:item><name>Harry Campbell MD</name><affiliations><json:string>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</json:string></affiliations></json:item><json:item><name>James F. Wilson DPhil</name><affiliations><json:string>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</json:string></affiliations></json:item><json:item><name>Alan F. Wright , PhD</name><affiliations><json:string>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</json:string></affiliations></json:item><json:item><name>Malcolm Dunlop MD</name><affiliations><json:string>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</json:string></affiliations></json:item><json:item><name>Giorgio Pistis MS</name><affiliations><json:string>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</json:string></affiliations></json:item><json:item><name>Daniela Toniolo PhD</name><affiliations><json:string>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</json:string><json:string>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</json:string></affiliations></json:item><json:item><name>Patrick F. Chinnery FMedSci</name><affiliations><json:string>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string><json:string>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item><json:item><name>Thomas Gasser MD</name><affiliations><json:string>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</json:string></affiliations></json:item><json:item><name>Thomas Klopstock MD</name><affiliations><json:string>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</json:string></affiliations></json:item><json:item><name>Thomas Meitinger MD</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string><json:string>Institute of Human Genetics, Technical University Munich, Munich, Germany</json:string></affiliations></json:item><json:item><name>Holger Prokisch PhD</name><affiliations><json:string>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</json:string><json:string>Institute of Human Genetics, Technical University Munich, Munich, Germany</json:string></affiliations></json:item><json:item><name>Douglass M. Turnbull MD, PhD</name><affiliations><json:string>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</json:string></affiliations></json:item></author><articleId><json:string>ANA21780</json:string></articleId><language><json:string>eng</json:string></language><abstract>Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798</abstract><qualityIndicators><score>7.289</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 783 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>0</keywordCount><abstractCharCount>1673</abstractCharCount><pdfWordCount>4301</pdfWordCount><pdfCharCount>28169</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>249</abstractWordCount></qualityIndicators><title>Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title><genre><json:string>article</json:string></genre><host><volume>66</volume><publisherId><json:string>ANA</json:string></publisherId><pages><total>7</total><last>798</last><first>792</first></pages><issn><json:string>0364-5134</json:string></issn><issue>6</issue><subject><json:item><value>Original Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8249</json:string></eissn><title>Annals of Neurology</title><doi><json:string>10.1002/(ISSN)1531-8249</json:string></doi></host><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1002/ana.21780</json:string></doi><id>2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/2BC3F834E82888B9EB2A98E42CFBDD319BDDB254/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/2BC3F834E82888B9EB2A98E42CFBDD319BDDB254/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/2BC3F834E82888B9EB2A98E42CFBDD319BDDB254/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2009</date></publicationStmt><notesStmt><note type="content">*Potential conflict of interest: Nothing to report.</note><note>European Neurological Society</note><note>Wellcome Trust/UK</note><note>Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society - No. HA‐215;</note><note>German National Genome Network of the German Ministry for Education and Research (NGFNplus)</note><note>Health Protection Agency UK</note><note>D.M.T.</note><note>Newcastle University Centre for Brain Ageing and Vitality</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title><author><persName><forename type="first">Matthias</forename><surname>Elstner</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation></author><author><persName><forename type="first">Christopher M.</forename><surname>Morris</surname></persName><roleName type="degree">PhD</roleName><affiliation>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Katharina</forename><surname>Heim</surname></persName><roleName type="degree">BSc</roleName><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Peter</forename><surname>Lichtner</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Andreas</forename><surname>Bender</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation></author><author><persName><forename type="first">Divya</forename><surname>Mehta</surname></persName><roleName type="degree">MSc</roleName><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Claudia</forename><surname>Schulte</surname></persName><roleName type="degree">MSc</roleName><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Manu</forename><surname>Sharma</surname></persName><roleName type="degree">PhD</roleName><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Gavin</forename><surname>Hudson</surname></persName><roleName type="degree">PhD</roleName><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Stefano</forename><surname>Goldwurm</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation></author><author><persName><forename type="first">Alessandro</forename><surname>Giovanetti</surname></persName><roleName type="degree">MSc</roleName><affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</affiliation></author><author><persName><forename type="first">Massimo</forename><surname>Zeviani</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</affiliation></author><author><persName><forename type="first">David J.</forename><surname>Burn</surname></persName><roleName type="degree">MD, FRCP</roleName><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Ian G.</forename><surname>McKeith</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Robert H.</forename><surname>Perry</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">E.</forename><surname>Jaros</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Rejko</forename><surname>Krüger</surname></persName><roleName type="degree">MD</roleName><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">H.‐Erich</forename><surname>Wichmann</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation></author><author><persName><forename type="first">Stefan</forename><surname>Schreiber</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</affiliation></author><author><persName><forename type="first">Harry</forename><surname>Campbell</surname></persName><roleName type="degree">MD</roleName><affiliation>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</affiliation></author><author><persName><forename type="first">James F.</forename><surname>Wilson</surname></persName><roleName type="degree">DPhil</roleName><affiliation>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</affiliation></author><author><persName><forename type="first">Alan F.</forename><surname>Wright</surname></persName><roleName type="degree">, PhD</roleName><affiliation>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</affiliation></author><author><persName><forename type="first">Malcolm</forename><surname>Dunlop</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</affiliation></author><author><persName><forename type="first">Giorgio</forename><surname>Pistis</surname></persName><roleName type="degree">MS</roleName><affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</affiliation></author><author><persName><forename type="first">Daniela</forename><surname>Toniolo</surname></persName><roleName type="degree">PhD</roleName><affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</affiliation><affiliation>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</affiliation></author><author><persName><forename type="first">Patrick F.</forename><surname>Chinnery</surname></persName><roleName type="degree">FMedSci</roleName><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Gasser</surname></persName><roleName type="degree">MD</roleName><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Klopstock</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation></author><author><persName><forename type="first">Thomas</forename><surname>Meitinger</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</affiliation></author><author><persName><forename type="first">Holger</forename><surname>Prokisch</surname></persName><roleName type="degree">PhD</roleName><note type="correspondence"><p>Correspondence: Institute of Human Genetics, Technical University Munich, Trogerstr. 32, 81675 Munich, Germany</p></note><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</affiliation></author><author><persName><forename type="first">Douglass M.</forename><surname>Turnbull</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation></author></analytic><monogr><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="pISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><idno type="DOI">10.1002/(ISSN)1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-12"></date><biblScope unit="volume">66</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="792">792</biblScope><biblScope unit="page" to="798">798</biblScope></imprint></monogr><idno type="istex">2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</idno><idno type="DOI">10.1002/ana.21780</idno><idno type="ArticleID">ANA21780</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2009</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. 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registered="yes">10.1002/ana.21780</doi><idGroup><id type="unit" value="ANA21780"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Original Article</title><title type="tocHeading1">Original Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2009 American Neurological Association</copyright><eventGroup><event type="manuscriptReceived" date="2009-01-10"></event><event type="manuscriptRevised" date="2009-06-09"></event><event type="manuscriptAccepted" date="2009-06-09"></event><event type="publishedOnlineAccepted" date="2009-06-18"></event><event type="firstOnline" date="2009-06-18"></event><event type="publishedOnlineFinalForm" date="2009-12-23"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.1 mode:FullText source:FullText result:FullText" date="2010-02-23"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" 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xml:lang="en"><fi>PDXK</fi> and PD</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Matthias</givenNames><familyName>Elstner</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af3"><personName><givenNames>Christopher M.</givenNames><familyName>Morris</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Katharina</givenNames><familyName>Heim</familyName><degrees>BSc</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Peter</givenNames><familyName>Lichtner</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" 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#af16"><personName><givenNames>Daniela</givenNames><familyName>Toniolo</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au26" creatorRole="author" affiliationRef="#af5 #af6"><personName><givenNames>Patrick F.</givenNames><familyName>Chinnery</familyName><degrees>FMedSci</degrees></personName></creator><creator xml:id="au27" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Thomas</givenNames><familyName>Gasser</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au28" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Thomas</givenNames><familyName>Klopstock</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au29" creatorRole="author" affiliationRef="#af1 #af17"><personName><givenNames>Thomas</givenNames><familyName>Meitinger</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au30" creatorRole="author" affiliationRef="#af1 #af17" corresponding="yes"><personName><givenNames>Holger</givenNames><familyName>Prokisch</familyName><degrees>PhD</degrees></personName><contactDetails><email normalForm="Prokisch@helmholtz-muenchen.de">Prokisch@helmholtz‐muenchen.de</email></contactDetails></creator><creator xml:id="au31" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Douglass M.</givenNames><familyName>Turnbull</familyName><degrees>MD, PhD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="DE" type="organization"><unparsedAffiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="GB" type="organization"><unparsedAffiliation>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="DE" type="organization"><unparsedAffiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="GB" type="organization"><unparsedAffiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="GB" type="organization"><unparsedAffiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="IT" type="organization"><unparsedAffiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="IT" type="organization"><unparsedAffiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af9" countryCode="DE" type="organization"><unparsedAffiliation>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af10" countryCode="DE" type="organization"><unparsedAffiliation>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af11" countryCode="GB" type="organization"><unparsedAffiliation>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af12" countryCode="GB" type="organization"><unparsedAffiliation>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af13" countryCode="GB" type="organization"><unparsedAffiliation>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af14" countryCode="GB" type="organization"><unparsedAffiliation>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af15" countryCode="IT" type="organization"><unparsedAffiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af16" countryCode="IT" type="organization"><unparsedAffiliation>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af17" countryCode="DE" type="organization"><unparsedAffiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</unparsedAffiliation></affiliation></affiliationGroup><fundingInfo><fundingAgency>European Neurological Society</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Wellcome Trust/UK</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society</fundingAgency><fundingNumber>HA‐215</fundingNumber></fundingInfo><fundingInfo><fundingAgency>German National Genome Network of the German Ministry for Education and Research (NGFNplus)</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Health Protection Agency UK</fundingAgency></fundingInfo><fundingInfo><fundingAgency>D.M.T.</fundingAgency></fundingInfo><fundingInfo><fundingAgency>Newcastle University Centre for Brain Ageing and Vitality</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:03645134:media:ana21780:ANA_21780_sm_SupplementalMaterial"></mediaResource><caption>Supplementary figures and tables</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><section xml:id="abs1-1"><title type="main">Objective</title><p>The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined.</p></section><section xml:id="abs1-2"><title type="main">Methods</title><p>We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts.</p></section><section xml:id="abs1-3"><title type="main">Results</title><p>We identified four differentially expressed genes located in PD candidate pathways, ie, <i>MTND2</i> (mitochondrial, <i>p</i> = 7.14 × 10<sup>−7</sup>), <i>PDXK</i> (vitamin B6/dopamine metabolism, <i>p</i> = 3.27 × 10<sup>−6</sup>), <i>SRGAP3</i> (axon guidance, <i>p</i> = 5.65 × 10<sup>−6</sup>), and <i>TRAPPC4</i> (vesicle transport, <i>p</i> = 5.81 × 10<sup>−6</sup>). We identified a DNA variant (<i>rs2010795</i>) in <i>PDXK</i> associated with an increased risk of PD in the German cohort (<i>p</i> = 0.00032). This association was confirmed in the British (<i>p</i> = 0.028) and Italian (<i>p</i> = 0.0025) cohorts individually and reached a combined value of <i>p</i> = 1.2 × 10<sup>−7</sup> (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44).</p></section><section xml:id="abs1-4"><title type="main">Interpretation</title><p>We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in <i>PDXK</i>, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798</p></section></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Potential conflict of interest: Nothing to report.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>PDXK and PD</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene</title></titleInfo><name type="personal"><namePart type="given">Matthias</namePart><namePart type="family">Elstner</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christopher M.</namePart><namePart type="family">Morris</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Medical Toxicology Centre, Wolfson Unit of Clinical Pharmacology, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katharina</namePart><namePart type="family">Heim</namePart><namePart type="termsOfAddress">BSc</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Lichtner</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andreas</namePart><namePart type="family">Bender</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Divya</namePart><namePart type="family">Mehta</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Claudia</namePart><namePart type="family">Schulte</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Manu</namePart><namePart type="family">Sharma</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gavin</namePart><namePart type="family">Hudson</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stefano</namePart><namePart type="family">Goldwurm</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alessandro</namePart><namePart type="family">Giovanetti</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Massimo</namePart><namePart type="family">Zeviani</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David J.</namePart><namePart type="family">Burn</namePart><namePart type="termsOfAddress">MD, FRCP</namePart><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ian G.</namePart><namePart type="family">McKeith</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Robert H.</namePart><namePart type="family">Perry</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">E.</namePart><namePart type="family">Jaros</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rejko</namePart><namePart type="family">Krüger</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">H.‐Erich</namePart><namePart type="family">Wichmann</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Stefan</namePart><namePart type="family">Schreiber</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Harry</namePart><namePart type="family">Campbell</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">James F.</namePart><namePart type="family">Wilson</namePart><namePart type="termsOfAddress">DPhil</namePart><affiliation>Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alan F.</namePart><namePart type="family">Wright</namePart><namePart type="termsOfAddress">, PhD</namePart><affiliation>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Malcolm</namePart><namePart type="family">Dunlop</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Giorgio</namePart><namePart type="family">Pistis</namePart><namePart type="termsOfAddress">MS</namePart><affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniela</namePart><namePart type="family">Toniolo</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan, Italy</affiliation><affiliation>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrick F.</namePart><namePart type="family">Chinnery</namePart><namePart type="termsOfAddress">FMedSci</namePart><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><affiliation>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Gasser</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Klopstock</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, Ludwig‐Maximilians‐University, Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Meitinger</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Holger</namePart><namePart type="family">Prokisch</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany</affiliation><affiliation>Institute of Human Genetics, Technical University Munich, Munich, Germany</affiliation><description>Correspondence: Institute of Human Genetics, Technical University Munich, Trogerstr. 32, 81675 Munich, Germany</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Douglass M.</namePart><namePart type="family">Turnbull</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2009-12</dateIssued><dateCaptured encoding="w3cdtf">2009-01-10</dateCaptured><dateValid encoding="w3cdtf">2009-06-09</dateValid><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">3</extent><extent unit="tables">2</extent><extent unit="references">27</extent><extent unit="words">4978</extent></physicalDescription><abstract lang="en">Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798</abstract><note type="content">*Potential conflict of interest: Nothing to report.</note><note type="funding">European Neurological Society</note><note type="funding">Wellcome Trust/UK</note><note type="funding">Impulse and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Health in an Ageing Society - No. HA‐215; </note><note type="funding">German National Genome Network of the German Ministry for Education and Research (NGFNplus)</note><note type="funding">Health Protection Agency UK</note><note type="funding">D.M.T.</note><note type="funding">Newcastle University Centre for Brain Ageing and Vitality</note><relatedItem type="host"><titleInfo><title>Annals of Neurology</title><subTitle>Official Journal of the American Neurological Association and the Child Neurology Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Ann Neurol.</title></titleInfo><genre type="Journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Supplementary figures and tables - </note><subject><genre>article category</genre><topic>Original Article</topic></subject><identifier type="ISSN">0364-5134</identifier><identifier type="eISSN">1531-8249</identifier><identifier type="DOI">10.1002/(ISSN)1531-8249</identifier><identifier type="PublisherID">ANA</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>66</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>792</start><end>798</end><total>7</total></extent></part></relatedItem><identifier type="istex">2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</identifier><identifier type="DOI">10.1002/ana.21780</identifier><identifier type="ArticleID">ANA21780</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2009 American Neurological Association</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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